Oxotremorine antagonist

ABSTRACT

The compound N-(5-pyrrolidino-3-pentynyl)-pyrrolidin-2-one or its therapeutically acceptable salts has been found to be a long lasting antagonist to the tremorogenic effects of oxotremorine.

United States Patent Dahlbom et al.

OXOTREMORINE ANTAGONIST Inventors: Johan Richard Dahlbom, Sodertalje;

Bo Lennart Karlen, Skarholmen; Sune Gunnar Lindgren, Linkoping, all of Sweden Assignee: Aktiebolaget Astra, Sodertalje,

Sweden Filed: Nov. 15, 1972 Appl. No.: 306,829

Published under the Trial Voluntary Protest Program on January 28, l975 as document no. B 306,829,

Related U.S. Application Data Continuation-impart of Ser, No. 203,907, Dec l, l97l abandoned, which is a continuation-in-part of Ser. No. 774,530, Nov. 8, 1968, abandoned Foreign Application Priority Data Nov. 9, I967 United Kingdom Sl l46/67 Dec. 9, 1975 U.S. Cl 260/326.25; 424/274 lnt. Cl. C07D 205/00 Field of Search 260/326.25

References Cited UNITED STATES PATENTS S/l969 Nau 260/32625 X Primary ExaminerR. Gallagher y. 8 mBrumbaugh, Graves. Donohue & Raymond [57} ABSTRACT 1 Claim, N0 Drawings OXOTREMORINE ANTAGONIST This is a continuation-in-part of our Ser. No. 203,907, filed Dec. 1, I97 I which was a continuationin-part of our Ser. No. 774,530, filed Nov. 8, 1968, both now abandoned.

The present invention relates to a new compound N-(-pyrrolidino-3-pentynyl)-pyrrolidin-2-one and its therapeutically acceptable salts. The compound is represented by the formula:

L Q/N-CH -CH -C C-CH -N For some years, oxotremorine [N-(4-pyrrolidino-2- butynyl)-pyrrolidin-2-one] has been used to induce tremors and spasticity in several species of laboratory animals. It induces violent generalized tremors, spasticity, hypokinesia and parasympathomimetic effects immediately after injection by intravenous routes and produces both central and peripheral cholinergic reactrons.

A number of drugs, such as atropine and caramiphen l-phenylcyclopentanecarboxylic acid 2-diethylaminoethyl ester), are known which will antagonize the oxotremorine-induced tremor. These drugs, however, have a relatively short pharmacological half-life and must be repeatedly administered in order to obtain a lasting antagonist action. The repeated administration of these drugs is undesirable since they have side effects which affect the peripheral nervous system. The compound of the present invention has been found to possess a long pharmacological half-life thereby making it suitable for use as a long-lasting oxotremorine antagonist.

When used as an oxotremorine antagonist, the compound N-(5-pyrrolidino-3-pentynyl)-pyrrolidin-2-one should preferably be in the free base form. It will be obvious to those skilled in the art, however, that in the preparation of the compound it may be convenient to prepare the non-toxic or therapeutically acceptable salts to simplify steps such as fractional crystallization. Accordingly, it will be understood that the typical therapeutically acceptable salts are included within the present invention. Such salts include, but are not limited to, the salts of the hydrohalides, especially hydrochloric and hydrobromic acid, and the salts of sulfuric acid, phosphoric acid, acetic acid, tartaric acid, citric acid, and succinic acid. The salts of hydrochloric and hydrobromic acids are preferred because of their ready availability. Manifestly, many other physiologically acceptable salts will be obvious to those skilled in the art, and all such salts may be employed in the present invention.

As is well-known in the art, the tremoromimetic effect of oxotremorine has been proposed as a pharmacological model of Parkinson's disease. The fact that the compound of the present invention has a long pharmacological half-life in antagonizing the tremoromimetic effect of oxotremorine suggests, therefore, that it might also be useful as a long-acting drug in the treatment of Parkinsons disease.

The pharmacological half-life of the compound of the claimed invention as an oxotremorine antagonist was compared with N-(5pyrrolidino-3-pentynyl) suc cinimide, a compound described in Dahlbom et al. US.

Pat. No. 3,444,171, in Example 14 (as a citrate) and as the ninth compound from the bottom in Table IV of that patent. The following test procedure was used.

Using screening data orally effective doses of the two above-mentioned compounds were chosen. Groups of six female mice weighing 22 to 26 grams were then administered oxotremorine without the test compounds to establish a control group and the median effective dose of oxotremorine needed to produce a spontaneous tremor was determined by the up-anddown" method for small samples described by W. J. Dixon in the Journal of the American S tatislical Association, 60: 967-978 (1965). The tremors in all mice were graded three minutes after intravenous administration of oxotremorine.

In the Dixon method the first animal is treated at an arbitrarily selected level and the presence or absence of tremor response is noted. An increased or decreased dosage is then selected for the second animal according to a schedule specified in the Dixon procedure which would tend to produce a change in the tremor response. (For example, if the initial dose produces a tremor, the second animal is treated at a reduced dosage to determine if no tremor will result.) The procedure is repeated until all six mice have been tested. If, following the sequence of testing specified by Dixon, all mice of the group showed the same tremor response (all negative or all positive), the group was increased until a change in response was found in two mice.

The orally effective dose of each of the test com pounds was then administered at varying times before administration of the oxotremorine to succeeding groups of six mice and the increased median effective dose of oxotremorine in the presence of the test compounds was determined in the same manner. The increase in dose of oxotremorine required to overcome the effect of the test compound, and to produce a constant biological response compared to the control group, measures quantitatively the effect of the test compound as an oxotremorine antagonist with time.

The compound of the present invention and the compound described in the Dahlbom et al. patent were administered orally. The dose of oxotremorine needed to produce tremors which were intermittent and occasional was determined for two dosage levels (i.e., 0.15 mM/kg and 0.05 mM/kg) of the compound of the present invention and one dosage level (i.e., 0.037 mM/kg) of N-(5-pyrrolidino-3-pentynyl) succinimide, the compound described in the Dahlbom et al. patent. The acid salt of the compound of the present invention (l mole compound 1.5 moles oxalic acid, mol. wt. of 355.5) was added to every 1 ml of water to give an appropriate pharmacological preparation (pH 3.75) for oral administration during testing. The hydrochloride salt of the Dahlbom et al. compound was tested. The dose of oxotremorine effective for the control group of mice was subtracted from the effective dose of oxotremorine determined at each of the various times after administration of each of the test compounds. Since the increase in dose of oxotremorine required to produce a spontaneous tremor is a measure of the degree of antagonism produced by the test compounds, the pharmacological half-life is determined as the time required to reduce the increase in the median effective dose of oxotremorine by one-half.

The Table given below shows the oxotremorine concentration in g/kg necessary to produce tremor in mice after previous administration of N-(5-pyrrolidino- S-pentynyl)pyrrolidin-Z-one. the compound of the present invention (labelled A in the Table) and N-(S- pyrrolidin-3-pentynyl) succinimidc (labelled B in the Table) disclosed in the Dahlbom et al patent.

Since a linear relationship should hold for disappearance of pharmacological effect (x=time, y is expressed as a logarithm function) and since the initial test is without the initial concentration of oxotremorine, the (control) was subtracted from the test concentrations of oxotremorine administered to arrive at the above data. A plot of log (A-a) [y axis] versus time (x axis) for each of the three series of tests was constructed and the best straight line was drawn through the points for each series. From the three lines the half-life was estimated.

It was found that the pharmacological half-life of the compound of the claimed invention is 28.4 minutes whereas the half-life of the prior art compound, N-(5- pyrrolidino-3-pentynyl) succinimide, is 12.4 minutes. The compound of the present invention achieved its peak effect within l0 minutes after oral administration whereas the Dahlbom et al. compound had its peak effect somewhere between 15 and 30 minutes after oral administration. The disappearance rate cannot be determined by the type of test used herein until after the peak effect has occurred. The data suggest that the compound of the present invention is more efficiently absorbed from the gastrointestinal tract than the compound described in the Dahlbom et al. patent.

The sesquioxalate of the compound of the present invention can be prepared by the following preferred reaction:

Five grams of N-(B-butynyl)-pyrrolidin-2-one were mixed with 1.2 g of formaldehyde, l0 ml of peroxidefree dioxane, 0.06 g of cuprous chloride and 2.6 g of pyrrolidine and heated with stirring at C. for one hour. The reaction product was isolated and purified as the sesquioxalate with a melting point of l l9l2lC.

It will become apparent that a person of skill in the art upon reading this specification will become aware of modifications and changes that can be made herein. Hence the foregoing is intended to be illustrative only. The claims define the invention.

We claim:

I. The compound N-(5-pyrrolidino-3-pentynyl)- pyrrolidin-Z-one or its therapeutically acceptable salts. 

1. THE COMPOUND N-(5-PYRROLIDINO-3-PENTYNYL)-PYRROLIDIN-2-ONE OR ITS THERAPEUTICALLY ACCEPTABLE SALTS. 